Research Institute of Immunobiology, Catholic Research Institute of Medical Science, Catholic University of Korea, Seoul 137-701, South Korea.
J Exp Med. 2012 Apr 9;209(4):871-86. doi: 10.1084/jem.20111783. Epub 2012 Mar 19.
An accumulation of misfolded proteins can trigger a cellular survival response in the endoplasmic reticulum (ER). In this study, we found that ER stress-associated gene signatures were highly expressed in rheumatoid arthritis (RA) synoviums and synovial cells. Proinflammatory cytokines, such as TNF and IL-1β, increased the expression of GRP78/BiP, a representative ER chaperone, in RA synoviocytes. RA synoviocytes expressed higher levels of GRP78 than osteoarthritis (OA) synoviocytes when stimulated by thapsigargin or proinflammatory cytokines. Down-regulation of Grp78 transcripts increased the apoptosis of RA synoviocytes while abolishing TNF- or TGF-β-induced synoviocyte proliferation and cyclin D1 up-regulation. Conversely, overexpression of the Grp78 gene prevented synoviocyte apoptosis. Moreover, Grp78 small interfering RNA inhibited VEGF(165)-induced angiogenesis in vitro and also significantly impeded synoviocyte proliferation and angiogenesis in Matrigel implants engrafted into immunodeficient mice. Additionally, repeated intraarticular injections of BiP-inducible factor X, a selective GRP78 inducer, increased synoviocyte proliferation and angiogenesis in the joints of mice with experimental OA. In contrast, mice with Grp78 haploinsufficiency exhibited the suppression of experimentally induced arthritis and developed a limited degree of synovial proliferation and angiogenesis. In summary, this study shows that the ER chaperone GRP78 is crucial for synoviocyte proliferation and angiogenesis, the pathological hallmark of RA.
蛋白质错误折叠的积累会触发内质网 (ER) 的细胞存活反应。在这项研究中，我们发现 ER 应激相关基因特征在类风湿关节炎 (RA) 滑膜和滑膜细胞中高度表达。促炎细胞因子，如 TNF 和 IL-1β，增加了 RA 滑膜细胞中 GRP78/BiP，一种代表性的 ER 伴侣蛋白的表达。当用 thapsigargin 或促炎细胞因子刺激时，RA 滑膜细胞表达的 GRP78 水平高于骨关节炎 (OA) 滑膜细胞。下调 Grp78 转录本增加了 RA 滑膜细胞的凋亡，同时消除了 TNF 或 TGF-β诱导的滑膜细胞增殖和 cyclin D1 上调。相反，Grp78 基因的过表达可防止滑膜细胞凋亡。此外，Grp78 小干扰 RNA 抑制了体外 VEGF(165)诱导的血管生成，并且在植入免疫缺陷小鼠的 Matrigel 植入物中也显著阻止了滑膜细胞增殖和血管生成。此外，内质网伴侣蛋白 X 的诱导物 BiP 的重复关节内注射，一种选择性的 GRP78 诱导物，增加了实验性 OA 小鼠关节中滑膜细胞的增殖和血管生成。相比之下，Grp78 杂合不足的小鼠表现出实验性关节炎的抑制作用，并发展出有限程度的滑膜增殖和血管生成。总之，这项研究表明内质网伴侣蛋白 GRP78 对于滑膜细胞的增殖和血管生成至关重要，这是 RA 的病理标志。
